US20140187793A1 - Processes for the preparation of 5-azaspiro[2.4]heptane-6-carboxylic acid and its derivatives - Google Patents

Processes for the preparation of 5-azaspiro[2.4]heptane-6-carboxylic acid and its derivatives Download PDF

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US20140187793A1
US20140187793A1 US14/082,406 US201314082406A US2014187793A1 US 20140187793 A1 US20140187793 A1 US 20140187793A1 US 201314082406 A US201314082406 A US 201314082406A US 2014187793 A1 US2014187793 A1 US 2014187793A1
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formula
compound
hydrogen
reagent
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US8927739B2 (en
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Yao-Ling Qiu
Xiaowen Peng
In Jong Kim
Hui Cao
Datong Tang
Yat Sun Or
Guoqiang Wang
Guoyou Xu
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Enanta Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/54—Spiro-condensed

Definitions

  • 4-spirocyclopropyl proline and its derivatives have been found to be useful intermediates in the preparation of reagents for the treatment of HCV infection (for example, see: WO02009/102325A1, WO02010/099527A1 and WO02010/132601A1).
  • the preparation of 4-spirocyclopropyl proline derivatives generally involves treatment of a 4-exocyclic methylene-substituted proline compound with a metal carbenoid generated through Simmon-Smith reaction or its different variations (e.g. Et 2 Zn/ClCH 2 I, Et 2 Zn/CH 2 I 2 /CF 3 COOH).
  • a preferred embodiment of a compound of Formula (I) is the compound of Formula (Ia):
  • the invention related to the preparation of a spiropropane compound of Formula (I, Ia, Ib or Ic), through addition of a dihalocarbene to an exocyclic olefinic double bond to give a dihalogenated cyclopropane intermediate, followed by reductive hydrodehalogenation.
  • the invention further relates to methods for increasing product yield and decreasing process steps for intermediate and large scale production of compounds of Formula (Ia) and particularly, (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid. These compounds are useful as reagents in the synthesis of HCV inhibitors, especially those that have been disclosed in WO2010/099527A1.
  • R is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably, R is hydrogen, optionally substituted C 1 -C 4 alkyl or optionally substituted aryl; more preferably, R is hydrogen, methyl, benzyl, tent-butyl or phenyl; and
  • R and PG are as previously defined;
  • X at each occurrence is independently selected from the group consisting of hydrogen, bromine and chlorine; wherein at least one of the two X groups is chlorine or bromine;
  • R and PG are as previously defined;
  • R is hydrogen, optionally substituted C 1 -C 4 alkyl or optionally substituted aryl; in yet another embodiment, R is hydrogen, methyl, benzyl, tent-butyl or phenyl.
  • X at each occurrence is independently hydrogen or bromine and at least one of the two X groups is bromine.
  • the dihalocarbene of step (c) is generated by thermal decomposition of a trihaloacetate salt, optionally in the presence of a halide or phase-transfer catalyst.
  • the trihaloacetate salt is sodium trichloroacetate or sodium tribromoacetate.
  • step (c) is conducted in the presence of a halide salt or a phase-transfer catalyst.
  • the halide salt is also a phase-transfer catalyst, such as a quaternary ammonium halide salt or a phosphonium halide salt.
  • step (d) comprises reacting the compound of Formula (V) with a reductive radical reagent or a single-electron reagent.
  • step (d) comprises reacting the compound of Formula (V) with a reductive radical reagent in the presence of a radical initiator.
  • the reductive radical reagent is a stannane, a silane, a sulfide, or a low-valent phosphorous compound.
  • the reductive radical reagent is tris(trimethylsilyl)silane or hypophosphorous acid (H 3 PO 2 ).
  • step (d) comprises reacting the compound of Formula (V) with a single electron transfer reagent.
  • the single electron transfer reagent is a low-valent metallic reagent.
  • the single electron transfer reagent used in step (d) is elemental Zn or Mg.
  • aryl refers to a mono- or polycyclic carbocyclic ring system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl.
  • a polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring.
  • Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof.
  • heteroaryl refers to a mono- or polycyclic aromatic radical having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized.
  • Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl.
  • a polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof.
  • C 2 -C 8 alkenyl refers to straight- or branched-chain hydrocarbon radicals containing from two to eight, or two to four carbon atoms, having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.
  • C 2 -C 8 alkynyl refers to straight- or branched-chain hydrocarbon radicals containing from two to eight, or two to four carbon atoms, having at least one carbon-carbon triple bond by the removal of a single hydrogen atom.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.
  • C 3 -C 8 cycloalkyl refers to a monocyclic or polycyclic saturated carbocyclic ring compound, and the carbon atoms may be optionally oxo-substituted.
  • Examples of C 3 -C 8 cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of C 4 -C 7 cycloalkyl include, but not limited to, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and the like.
  • C 3 -C 8 cycloalkenyl refers to monocyclic or polycyclic carbocyclic ring compound having at least one carbon-carbon double bond and the carbon atoms may be optionally oxo-substituted.
  • C 3 -C 8 cycloalkenyl examples include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like; and examples of C 5 -C 7 cycloalkenyl include, but not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.
  • any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic and cycloalkenyl moiety described herein can also be an aliphatic group or an alicyclic group.
  • An “aliphatic” group is a non-aromatic moiety comprised of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contains one or more units of unsaturation, e.g., double and/or triple bonds.
  • aliphatic groups are functional groups, such as, O, OH, NH, NH 2 , C(O), S(O) 2 , C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH 2 , S(O) 2 NH, S(O) 2 NH 2 , NHC(O)NH 2 , NHC(O)C(O)NH, NHS(O) 2 NH, NHS(O) 2 NH 2 , C(O)NHS(O) 2 , C(O)NHS(O) 2 NH or C(O)NHS(O) 2 NH 2 , and the like, groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a functional group.
  • functional groups such as, O, OH, NH, NH 2 , C(O), S(O
  • Carbon atoms of an aliphatic group can be optionally oxo-substituted.
  • An aliphatic group may be straight chained, branched, cyclic, or a combination thereof and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms.
  • aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Aliphatic groups may be optionally substituted.
  • a linear aliphatic group is a non-cyclic aliphatic group.
  • an aliphatic group or a linear aliphatic group when said to “contain” or “include” or “comprise” one or more specified functional groups, the linear aliphatic group can be selected from one or more of the specified functional groups or a combination thereof, or a group wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a specified functional group.
  • an exemplary linear aliphatic group is an alkyl, alkenyl or alkynyl, each optionally substituted, which is interrupted or terminated by a functional group such as described herein.
  • heterocyclic or “heterocycloalkyl” can be used interchangeably and referred to a non-aromatic ring or a bi- or tri-cyclic group fused system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted.
  • heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted. Heteroaryl or heterocyclic groups can be C-attached or N-attached (where possible).
  • any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety or the like, described herein can also be a divalent or multivalent group when used as a linkage to connect two or more groups or substituents, which can be at the same or different atom(s).
  • substituted refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, —F, —Cl, —Br, —I, —OH, protected hydroxy, —NO 2 , —N 3 , —CN, —NH 2 , protected amino, oxo, thioxo, —NH—C 1 -C 12 -alkyl, —NH—C 2 -C 8 -alkenyl, —NH—C 2 -C 8 -alkynyl, —NH—C 3 -C 12 -cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, —O—C 1 -C 12 -alkyl, —O—C 2
  • halogen refers to an atom selected from fluorine, chlorine, bromine and iodine.
  • hydrox includes hydrogen and deuterium.
  • recitation of an atom includes other isotopes of that atom so long as the resulting compound is pharmaceutically acceptable.
  • the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d.
  • the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • the compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art.
  • any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon-heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.
  • Suitable concentrations of reactants used in the synthesis processes of the invention are 0.01M to 10M, typically 0.1M to 1M.
  • Suitable temperatures include ⁇ 10° C. to 250° C., typically ⁇ 78° C. to 150° C., more typically ⁇ 78° C. to 100° C., still more typically 0° C. to 100° C.
  • Reaction vessels are preferably made of any material which does not substantial interfere with the reaction. Examples include glass, plastic, and metal.
  • the pressure of the reaction can advantageously be operated at atmospheric pressure.
  • the atmospheres include, for example, air, for oxygen and water insensitive reactions, or nitrogen or argon, for oxygen or water sensitive reactions.
  • situ refers to use of an intermediate in the solvent or solvents in which the intermediate was prepared without removal of the solvent.
  • Olefin (IV) is then converted to dihalogenated cyclopropane (V) by reaction with a dihalocarbene, preferably generated via thermal decomposition of a trihaloacetate salt, optionally in the presence of a halide salt or phase-transfer catalyst, as is known to those skilled in the art.
  • a dihalocarbene preferably generated via thermal decomposition of a trihaloacetate salt, optionally in the presence of a halide salt or phase-transfer catalyst, as is known to those skilled in the art.
  • the hydrodehalogenation of the dihalogenated cyclopropane (V) to the title cyclopropane (I) can be carried out under reductive radical conditions or single electron transfer conditions.
  • Compounds of Formula (1-2) may be synthesized by reacting compounds of Formula (1-1) (which are either commercially available or may be synthesized by methods known to those skilled in the art) with an oxidizing reagent, such as TEMPO/NaClO, PDC, Dess-Martin periodinane, and that used in Swern oxidation or Corey-Kim oxidation.
  • an oxidizing reagent such as TEMPO/NaClO, PDC, Dess-Martin periodinane, and that used in Swern oxidation or Corey-Kim oxidation.
  • Compounds of Formula (1-2) may be converted to compounds of Formula (1-3) by olefination through a Wittig reaction or related reactions, in the presence of a strong base.
  • the typical Wittig reagents or related reagents may include Ph 3 PCH 3 Br, Ph 3 PCH 3 I, (EtO) 2 P(O)CH 3 , Me 3 SiCH 2 Cl, or their corresponding polymer-supported forms.
  • Examples of the base may include potassium t-butoxide, lithium t-butoxide, sodium methoxide, sodium ethoxide, LDA, LiHMDS, NaHMDS, and KHMDS.
  • the typical reaction temperature is between ⁇ 78° C. to 100° C. and the typical duration of the reaction is 1 to 48 hours.
  • compounds of Formula (1-2) may be treated with a metallated carbene reagent, such as Tebbe reagent or Lombardo reagent to provide compounds of Formula (1-3).
  • a metallated carbene reagent such as Tebbe reagent or Lombardo reagent
  • Compounds of Formula (1-4) may be prepared by reacting compounds of Formula (1-3) with an alkylating reagents in the presence of a base.
  • bases include, but not limited to, potassium carbonate, sodium bicarbonate, sodum hydroxide, triethylamine, diisopropylethylamine, hexamethyldisilane, and DBU.
  • compounds of Formula (1-4) may prepared by reacting compounds of Formula (1-3) with an alcohol in the presence of a condensation reagent or water scavenger such as DCC, EDC or the like, optionally in the presence of a base.
  • a condensation reagent or water scavenger such as DCC, EDC or the like
  • compounds of Formula (1-3) may be converted to compounds of Formula (1-4) in two steps: 1) mixed anhydride formation between compounds of Formula (1-3) with an acid chloride such as 2,4,6-trichlorobenzoyl chloride, or the like, or a chloroformate such as methyl chloroformate, isobutyl chloroformate, or the like, in the presence of a base such as TEA, DIPEA, DMAP, N-methylmorpholine, or the like; 2) treating the mixed anhydride with an alcohol to afford compounds of Formula (1-3).
  • an acid chloride such as 2,4,6-trichlorobenzoyl chloride, or the like
  • a chloroformate such as methyl chloroformate, isobutyl chloroformate, or the like
  • a base such as TEA, DIPEA, DMAP, N-methylmorpholine, or the like
  • Compounds of Formula (1-4) may be converted to compounds of Formula (1-5) by reacting with a monohalocarbene or a dihalocarbene, which may be generated by treating dichloromethane, dibromomethane, chloroform or bromoform with a base, optionally in the presence of a phase-transfer catalyst.
  • the base is typically NaOH, KOH, t-BuOK, or the like.
  • phase-transfer catalyst may include, but not limited to, Bu 4 NCl, Bu 4 NBr, Bu 4 NI, Et 3 BnNBr, and crown ethers.
  • compounds of Formula (1-5) may be prepared by reacting compounds of Formula (1-4) with a dihalocarbene generated through the thermal decomposition of a trihaloacetate salt, such as Cl 3 CCO 2 Na, Br 3 CCO 2 Na, optionally in the presence of a halide salt or a phase-transfer catalyst; preferably the halide salt may be also a phase-transfer catalyst.
  • the reaction temperature is typically between 20-200° C. and the reaction time is typically between 1 to 48 hours.
  • phase-transfer catalysts include Bu 4 NCl, Bu 4 NBr, Bu 4 NI, Et 3 BnNBr, and crown ethers.
  • Compounds of Formula (I) may be prepared by reductive hydrodehalogenation of compounds of Formula (1-5) with a low valent metal, preferably in a protic solvent or a combination of protic solvents.
  • a low valent metal preferably in a protic solvent or a combination of protic solvents.
  • the reduction may be performed with a low valent metal in the presence of an electron absorbing reagent, such as naphthalene, in a aprotic solvent or a combination of aprotic solvents.
  • the low valent metal include Zn, Mg, Li, Na, K, and Ti metal.
  • the solvents typically used include but not limited to water, HOAc, MeOH, t-BuOH.
  • a compound of Formula (1-5) may be converted to a compound of Formula (I) with a reductive radical reagent in the presence of a radical initiator.
  • radical reducing reagents include, but not limited to, stannanes, silanes, low-valent phosphorous and sulfur compounds, such as Bu 3 SnH, (Me 3 Si) 3 SiH, H 3 PO 2 , and the like.
  • the initiator is typically AIBN, BPO, or a water-soluble radical initiator such as V-50 or VA-44.
  • the solvents used in the reaction may be protic or aprotic solvents.
  • the reaction is typically conducted at a temperature between 20-200° C. and the reaction time is typically between 1 and 100 hours.
  • the reductive radical reagent is (Me 3 Si) 3 SiH or H 3 PO 2 .
  • some of the reductive radical reactions described above may be performed catalytically with excess of another reducing reagent.
  • another reducing reagent such as tetrabutylammonium tetrahydroborate.
  • compounds of Formula (I) where R is not hydrogen may be converted to compounds of Formula (Ia) by removing the R group via deprotective hydrolysis.
  • compounds of Formula (1-5) may be converted to compounds of Formula (Ia) through intermediate (1-6) by switching the order of deprotection and hydrodehalogenation using procedures similar to those described above.
  • compounds of Formula (I) where PG is not hydrogen may be converted to compounds of Formula (Ib) by removing the protective PG group.
  • Reaction conditions vary depending on the identity of PG and the choice of the deprotecting reagent and will be known to those skilled in the art, and are described generally in T. H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
  • compounds of Formula (I) where neither R nor PG is hydrogen may be converted to compounds of Formula (Ic) by removing the R group via hydrolysis and by removing the PG group as described above.
  • the R and PG groups can be removed in either order, or, in certain embodiments, they can be removed simultaneously.
  • the aqueous layer was acidified with 6N HCl (100 mL), extracted with ethyl acetate (1 L and 0.8 L). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated to dryness. The residue was dissolved in 50% ethyl acetate in cyclohexane (150 mL), slowly evaporated to give a yellowish solid. It was filtered and dried to give the title compound (26 g). The filtrate was evaporated to give a yellowish solid, filtered and dried to provide the title compound (10 g). Total 36 g (65%) as a white solid. Also, the residue contained 18 g of the product as 80% purity.
  • the aqueous layer was extracted with ethyl acetate (300 and 200 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 solution (100 mL), water (3 ⁇ 200 mL) and brine, dried (Na 2 SO 4 ), filtered and evaporated to dryness. The residue was passed through a silica gel (2 wt. volumes) pad with 0-15% ethtyl acetate in hexanes to afford the title compound (37.06 g, quantitative yield) as a colorless oil.
  • the residue was diluted with 30% hexanes in tert-butyl methyl ether (100 mL) and filtered through a pad of celite. The filtrate was washed with water and brine, dried (Na 2 SO 4 ), filtered and evaporated to dryness. The residue was passed through a silica gel (5.5 wt. volumes) pad with 0-15% tert-butyl methyl ether in hexanes and concentrated to afford the title compound (9.09 g, 88%) as a yellow oil as a mixture of two regioisomers.

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WO2012158861A3 (en) 2013-01-10
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